We searched PubMed using the terms “thalassaemia” in combination with “molecular basis” or “treatment” or “pathophysiology”. We mostly selected publications from from June 2006, to June 2011, but did not exclude frequently referenced and highly regarded older publications. We also searched the reference lists of articles identified by this search strategy and selected the most relevant ones. Review articles and book chapters are cited to provide readers with more details and more references
SeminarThalassaemia
Introduction
Abnormalities in the structure and synthesis of the α-like and β-like globin chains that form tetramers of haemoglobin (α2β2) lead to the most common forms of inherited anaemias.1 In thalassaemia, there are defects in the production of either the α-like (α-thalassaemia2) or the β-like (β-thalassaemia3) globin chains. From the 1970s, these diseases, which specifically affect red blood cells, were among the first to be analysed with the use of molecular biology. Their detailed characterisation has established many of the general principles supporting our understanding of human molecular genetics.4 Furthermore, research into globin genes has greatly contributed to the understanding of how human gene expression is activated and silenced during differentiation and development.5, 6, 7, 8 Despite these advances, manipulation of globin gene expression to ameliorate or potentially cure the common disorders of these genes is not yet possible. Every 2 years since 1978, leading research groups have met at the Hemaglobin Switching Conference to report and discuss progress. In this Seminar we will summarise the understanding of the molecular and cellular pathophysiology, epidemiology, and management of β-thalassaemia, which is the main clinical problem in this specialty.1 We also review the developments reported at the 17th Hemaglobin Switching Conference in Oxford, UK, which offer renewed hope for novel approaches to treat these disorders.
Section snippets
Production of red blood cells
To fully understand the pathophysiology and management of thalassaemia, how red blood cells are normally produced (erythropoiesis), and how the globin genes are normally expressed at each stage of development should be considered. First, a transient cohort of embryonic red blood cells originate in the blood islands of the yolk sac. Definitive haemapoietic stem cells (HSCs), which persist throughout fetal and adult life, then emerge from the ventral wall of the dorsal aorta. These cells migrate
Normal expression of globin genes
Changes in the sites of erythropoiesis are associated with changes in the types of haemoglobin produced. At the molecular level, haemoglobin synthesis is controlled by two multigene clusters on chromosome 16 (encoding the α-like globins) and on chromosome 11 (encoding the β-like globins). In the human clusters, the genes are arranged along the chromosome in the order by which they are expressed during development to produce different haemaglobin tetramers: embryonic (Hb Gower-I [ζ2ɛ2], Hb
Variants that alter expression of globin genes
More than 200 β-thalassaemia alleles have been described in the database of human haemaglobin variants and thalassaemias, which involve mutations in any of the stages from transcription to RNA processing and translation of β-globin mRNA (figure 3).23 These mutations are detectable by DNA analysis and provide the basis for genetic counselling.24 Although most β-thalassaemias are caused by point mutations in the gene or its immediate flanking region, small deletions removing the β gene can also
The molecular and cellular pathology of β-thalassaemia
At each stage of development, the production of α-like and β-like globins is balanced. β-globin synthesis is normally controlled by the two β genes (one on each copy of chromosome 11). A mutation affecting one gene (β/βT or β-thalassaemia trait) usually causes no clinically significant problem, whereas patients who inherit deleterious mutations in both β genes (βT/βT) frequently have severe anaemia. The main pathophysiology in β-thalassaemia results from the synthesis of insufficient β chains
Epidemiology
WHO has estimated that about 1·5% of the world's population might be carriers of β-thalassaemia (β/βT) and that about 60 000 severely affected infants are born every year.44 These individuals mostly originate from the Mediterranean, Middle East, central Asia, India, and southern China, which suggests that there could be a selective advantage to carrying such a mutation in these areas. Similar observations have been made for α thalassaemia,1 which is even more widely distributed and more
Clinical phenotypes and standard management
The three broad clinical phenotypes in patients with β thalassaemia are major, intermedia, and minor. These phenotypes are associated with more than 200 different mutations that either reduce (β+-thalassaemia) or abolish (β0-thalassaemia) expression of the affected β-globin genes. Thalassaemia major occurs in homozygotes (βT/βT) or compound heterozygotes (eg, βT/βE) for such mutations. Affected individuals usually present with pallor, hepatosplenomegaly, and failure to thrive in the first year
Genetic testing and prenatal diagnosis
Initial screening of populations and identification of families at risk of producing infants who are affected by β thalassaemia has been achieved by examination of red-blood-cell indices and analysis of haemaglobin. The techniques to identify specific mutations underlying β thalassaemia in DNA from adults and fetuses are now well established and extensively applied to genetic counselling and prenatal diagnosis.24 New non-invasive techniques to analyse fetal DNA in the maternal circulation are
Pharmacological agents used to treat thalassaemia
The aims of therapeutic interventions for β thalassaemia are to increase expression of γ globin or to decrease expression of α globin, thus restoring the balance between α-like and β-like globin chains. Much evidence from clinical genetic studies shows that either (or preferably both) of these manipulations would have substantial clinical belenfits in patients with β thalassaemia.7, 12, 43, 63 Pharmacological studies have all focused on increasing expression of γ globin, but have been based on
Stem-cell transplantation for thalassaemia
In the past 30 years, stem-cell transplantation has substantially advanced treatment of thalassaemia major.67 Children who are identified before developing viral hepatitis or severe iron overload and who receive HLA-identical related donor stem-cell transplants have a very high likelihood of remission, with less than 10% mortality and minimal morbidity, apart from impaired fertility.67 Most groups report event-free survival of 80–90% for β thalassaemia.67, 69, 70, 71, 72 By contrast, event-free
Gene therapy for β thalassaemia
Thalassaemia was among the first genetic diseases for which gene therapy was proposed.82 This disorder is to some extent a good target because defects in expression of globin genes affect only the haemopoietic system and specifically affect erythropoiesis. Stem-cell transplantation is well developed for the haemapoietic system; however, unlike many genetic diseases, very high levels of tissue-specific gene expression are necessary to correct the globin defect in β thalassaemia. In principle,
Beyond gene therapy
In 2007, a landmark report96 described how human somatic cells (eg, skin fibroblasts) could be reprogrammed to form multipotent cells resembling embryonic stem cells. These reprogrammed cells are called induced pluripotent stem (iPS) cells.96, 97 Generation of iPS cells involves the introduction and expression of four transcription factors (Oct4, Sox2, KLF4, and c-Myc) in somatic cells. These transcription factors are normally needed to establish and maintain pluripotency. iPS cells have
Conclusions
Despite intensive clinical and scientific investigation of thalassaemia—a molecular disease that is perhaps better understood than any other—attempts to improve its management and to develop targeted drug therapy have not yielded a clear breakthrough. Stem-cell transplantation is an effective cure but still has a substantial risk of mortality and morbidity. Supportive results from cord-blood transplantation should encourage the development of cord-blood banking to address this issue. Gene
Search strategy and selection criteria
References (99)
The inherited diseases of hemoglobin are an emerging global health burden
Blood
(2010)- et al.
Locus control regions
Blood
(2002) - et al.
β-globin regulation and long-range interactions
Adv Genet
(2008) - et al.
Developmental- and differentiation-specific patterns of human γ- and β-globin promoter DNA methylation
Blood
(2007) - et al.
Epigenetics of β-globin gene regulation
Mutat Res
(2008) - et al.
Three-dimensional organization of gene expression in erythroid cells
Curr Top Dev Biol
(2008) Control of globin gene expression during development and erythroid differentiation
Exp Hematol
(2005)Screening and genetic diagnosis of haemoglobin disorders
Blood Rev
(2003)- et al.
ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner
Cell
(2010) - et al.
The population genetics and dynamics of the thalassemias
Hematol Oncol Clin North Am
(2010)
Thalassaemia: clinical management
Baillieres Clin Haematol
A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia
Blood
Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta-thalassemia
Blood
Hematopoietic cell transplantation for hemoglobinopathies
Curr Probl Pediatr Adolesc Health Care
Hematopoietic stem cell transplantation for hemoglobinopathies: current practice and emerging trends
Pediatr Clin North Am
Unrelated donor bone marrow transplantation for thalassemia: the effect of extended haplotypes
Blood
Advances in the allogeneic transplantation for thalassemia
Blood Rev
Cord blood transplantation in patients with hemoglobinopathies
Transfus Apher Sci
Rapid and complete donor chimerism after unrelated mismatched cord blood transplantation in 5 children with β-thalassemia major
Biol Blood Marrow Transplant
Update on gene therapy for immunodeficiencies
Clin Immunol
The degree of phenotypic correction of murine β-thalassemia intermedia following lentiviral-mediated transfer of a human γ-globin gene is influenced by chromosomal position effects and vector copy number
Blood
Successful treatment of murine β-thalassemia intermedia by transfer of the human β-globin gene
Blood
A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human β-globin gene transfer
Blood
Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors
Cell
α-thalassaemia
Orphanet J Rare Dis
Beta-thalassemia
Orphanet J Rare Dis
Towards molecular medicine; reminiscences of the haemoglobin field, 1960–2000
Br J Haematol
Hemoglobin switching
Long-range regulation of alpha globin gene expression during erythropoiesis
Curr Opin Hematol
A developmental approach to hematopoiesis
Ontogeny of erythropoiesis
Curr Opin Hematol
Erythropoiesis
The thalassaemia syndromes
Fine tuning of globin gene expression by DNA methylation
PLoS One
Intergenic transcription, cell-cycle and the developmentally regulated epigenetic profile of the human beta-globin locus
PLoS One
The language of covalent histone modifications
Nature
Transcriptional regulation of erythropoiesis: an affair involving multiple partners
Oncogene
Advances in the understanding of haemoglobin switching
Br J Haematol
Insulators: exploiting transcriptional and epigenetic mechanisms
Nat Rev Genet
Systematic documentation and analysis of human genetic variation in hemaglobinopathies using the microattribution approach
Nat Genet
The hemoglobin E syndromes
Ann N Y Acad Sci
γδβ-thalassemia due to a de novo mutation deleting the 5′ β-globin gene activation-region hypersensitive sites
Proc Natl Acad Sci USA
β-globin gene inactivation by DNA translocation in γ β-thalassaemia
Nature
Molecular basis of hereditary persistence of fetal hemoglobin
Ann N Y Acad Sci
The molecular basis of β thalassemia, δβ thalassemia and hereditary persistence of fetal hemoglobin
Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin
Nat Genet
GATA transcription factors in hematologic disease
Int J Hematol
KLF1 regulates BCL11A expression and γ- to β-globin gene switching
Nat Genet
Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation
Nat Genet
Cited by (366)
Identification and characterization of CHD4-associated eRNA as a novel modulator of fetal hemoglobin levels in β-thalassemia
2024, Biochemical and Biophysical Research CommunicationsMetabolic regulation of erythrocyte development and disorders
2024, Experimental HematologyThe incredible ULK improves β-thalassemia
2023, BloodRed blood cell alloimmunizations in thalassaemia patients with regular transfusion in China: A systematic review and meta-analysis
2023, Transfusion Clinique et Biologique